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Research Article

Loss of the golgin GM130 causes Golgi disruption, Purkinje neuron loss, and ataxia in mice

Chunyi Liu, Mei Mei, Qiuling Li, View ORCID ProfilePeristera Roboti, Qianqian Pang, Zhengzhou Ying, Fei Gao, Martin Lowe, and Shilai Bao
PNAS January 10, 2017 114 (2) 346-351; first published December 27, 2016; https://doi.org/10.1073/pnas.1608576114
Chunyi Liu
aState Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China;
bSchool of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China;
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Mei Mei
aState Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China;
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Qiuling Li
aState Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China;
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Peristera Roboti
cFaculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, United Kingdom;
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  • ORCID record for Peristera Roboti
Qianqian Pang
aState Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China;
bSchool of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China;
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Zhengzhou Ying
aState Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China;
bSchool of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China;
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Fei Gao
dState Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
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Martin Lowe
cFaculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, United Kingdom;
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  • For correspondence: slbao@genetics.ac.cn martin.lowe@manchester.ac.uk
Shilai Bao
aState Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China;
bSchool of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China;
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  • For correspondence: slbao@genetics.ac.cn martin.lowe@manchester.ac.uk
  1. Edited by Jennifer Lippincott-Schwartz, Howard Hughes Medical Institute, Ashburn, VA, and approved November 28, 2016 (received for review May 27, 2016)

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Significance

It has been known for many years that the Golgi apparatus, the central organelle of the secretory pathway, is fragmented upon neurodegenerative disease. However, it has remained an open question whether Golgi disruption contributes to neuronal death, as seen in disease, or is simply a consequence of this process. Here, we show that knocking out the Golgi protein GM130 in mice causes Golgi fragmentation and impaired secretory trafficking in Purkinje neurons, resulting in cell death and ataxia. The cell death and ataxia are first observed in postnatal development, but worsen with age. These findings indicate that targeted disruption of the Golgi apparatus can result in neuronal loss in vivo, supporting the view that Golgi dysfunction can contribute to neurodegeneration.

Abstract

The Golgi apparatus lies at the heart of the secretory pathway where it is required for secretory trafficking and cargo modification. Disruption of Golgi architecture and function has been widely observed in neurodegenerative disease, but whether Golgi dysfunction is causal with regard to the neurodegenerative process, or is simply a manifestation of neuronal death, remains unclear. Here we report that targeted loss of the golgin GM130 leads to a profound neurological phenotype in mice. Global KO of mouse GM130 results in developmental delay, severe ataxia, and postnatal death. We further show that selective deletion of GM130 in neurons causes fragmentation and defective positioning of the Golgi apparatus, impaired secretory trafficking, and dendritic atrophy in Purkinje cells. These cellular defects manifest as reduced cerebellar size and Purkinje cell number, leading to ataxia. Purkinje cell loss and ataxia first appear during postnatal development but progressively worsen with age. Our data therefore indicate that targeted disruption of the mammalian Golgi apparatus and secretory traffic results in neuronal degeneration in vivo, supporting the view that Golgi dysfunction can play a causative role in neurodegeneration.

  • GM130
  • Golgi apparatus
  • polarized secretion
  • Purkinje cell
  • ataxia

Footnotes

  • ↵1C.L., M.M., and Q.L. contributed equally to this work.

  • ↵2To whom correspondence may be addressed. Email: slbao{at}genetics.ac.cn or martin.lowe{at}manchester.ac.uk.
  • Author contributions: C.L., M.M., P.R., F.G., M.L., and S.B. designed research; C.L., M.M., Q.L., P.R., Q.P., and Z.Y. performed research; C.L., M.M., Q.L., P.R., Q.P., Z.Y., and S.B. analyzed data; and M.L. and S.B. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1608576114/-/DCSupplemental.

Freely available online through the PNAS open access option.

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Loss of GM130 causes ataxia in mice
Chunyi Liu, Mei Mei, Qiuling Li, Peristera Roboti, Qianqian Pang, Zhengzhou Ying, Fei Gao, Martin Lowe, Shilai Bao
Proceedings of the National Academy of Sciences Jan 2017, 114 (2) 346-351; DOI: 10.1073/pnas.1608576114

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Loss of GM130 causes ataxia in mice
Chunyi Liu, Mei Mei, Qiuling Li, Peristera Roboti, Qianqian Pang, Zhengzhou Ying, Fei Gao, Martin Lowe, Shilai Bao
Proceedings of the National Academy of Sciences Jan 2017, 114 (2) 346-351; DOI: 10.1073/pnas.1608576114
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